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Epidemiology ofAR
The prevalence of AR varies widely around the
world [1] (Fig.20.3).
Rates vary between 2 and 40% of the population around the world, with prevalence in Europe
varying between 20 and 40% [2]. The WHO estimates that 500million people in the world suffer
from AR, making it the third most prevalent
chronic disease in adults and the most prevalent
chronic disease in children.
The prevalence of allergic disease in general
has increased signicantly over the last century,
particularly in the industrialised world, but the reasons for this are not entirely clear. The hygiene
hypothesis suggests that reduced exposure to
microbes in early life, and a genetic predisposition
to atopy, has caused the immune system to become
dysregulated with a consequent excess production
of IgE and therefore expression of allergic symptoms. Protection against parasitic infection (which
is the underlying reason for mammals to express
IgE) may also be involved. Infestation with worms
has a strong protective effect against developing
allergy, probably by the production of blocking
IgG antibodies and the release of helminth-produced anti-inammatory chemicals that block
cytokines such as IL33, which drive the inammatory process. Worm infestation remains very prevalent in developing countries where there is
generally a low burden of allergic disease.
Clearly, sensitisation also depends on exposure to a potential allergen. This varies around
the world with countries near the equator having
less seasonal variation in allergens, and cooler,
damper countries having higher levels of exposure to indoor allergens. The physical size of the
allergen also plays a role, with larger particles
tending to be deposited in the nose and smaller
ones penetrating into the lower respiratory tract.
AR has been subdivided into two main
groups—intermittent AR (IAR) and persistent
Fig. 20.3 Map of prevalence of current symptoms of rhinoconjunctivitis, 13- to 14-year age group. Symbols indicate prevalence categories of ≥20% (red stars), ≥10 to
<20% (yellow diamonds) and <10% (blue squares)
(reproduced with permission from John Wiley and Sons)
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Q. Gardiner
Intermittent symptoms
< 4 days/week
< 4 weeks/episode
Mild
Normal sleep
Normal work and school
Normal daily activity
No disturbing symptoms
Fig. 20.4 ARIA classication of AR (reproduced with permission from Springer Nature)
AR (PER), and into mild or moderate/severe
(Fig. 20.4) [3]. Approximately 75% of patients
have a PER.
In Europe, the principal allergens causing IAR
are tree pollen in the spring, grass pollen in summer, and moulds and spores in the autumn. PER
is caused by house dust mite (HDM) allergen and
HDM faeces, cockroach and pet allergens (such
as dog and cat), which are mainly enzymes in the
dried saliva or urine in their fur. People may also
be exposed to a variety of allergens because of
their occupation. Food allergies have also become
more common, but while they may have an effect
or
Moderate to severe
(one or more points applicable)
activity is increased, leading to an increase in
asthma symptoms. Patients with AR and asthma
have twice the rate of requiring oral corticosteroids
or urgent care for an exacerbation of their symptoms than do asthmatic patients without AR [4].
There are also links with the effects of treatment. It seems that adequate treatment of nasal
disease can reduce exacerbations of asthma
requiring oral steroids or hospital admission, and
in some cases of mild AR and asthma that treatment of the nose alone may allow good symptom
control of asthma without inhaled steroids being
required at all.
Persistent symptoms
≥ 4 days/week
≥ weeks/episode
Disturbed sleep
Problem at work and school
Impairment of daily activity and sports
Disturbing symptoms
on the nose, their principal symptoms will be in
the gastrointestinal system.
Clinical Presentation: Symptoms
andQuality ofLife
AR andAsthma
The diagnosis of AR rests on the history, nasal
The term ‘unied allergic airway’ refers to the
underlying similarity of the mucosa of the upper
and lower respiratory tracts and the reactions that
occur when exposed to allergens. In patients with
allergic asthma, 65% will have a symptomatic
AR.In patients with AR, approximately 25% will
have asthma. The inammatory mediators released
in the nose have systemic as well as local effects.
The effect is also more marked because of
reduced nasal function. Apart from ltering the air
and reducing the quantity of allergen reaching the
lungs, the nose also warms and humidies the air.
If the nose is blocked and the patient breathes by
mouth, these functions are lost; bronchial hyperre-
examination and diagnostic tests, but of these the
history is usually the most useful.
The classic symptoms of AR are of cycling nasal
blockage, clear nasal discharge, itching and sneezing. The vast majority of patients will complain of
two or more of these symptoms. Although smell
may be affected, this is not usually mentioned
unless specically asked about, and most patients
with AR retain at least some sense of smell.
Secondary symptoms may also be noted such as
itchy eyes, throat and ears and dry mouth and halitosis (due to mouth breathing). Sometimes patients
may have a wheeze (particularly in peak allergen
season) and this should be asked about specically.
and
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The nasal block is often variable, cycling from
side to side. A xed block is more likely to be due
to an anatomical abnormality such as septal deviation or nasal polyps. The discharge is usually
clear and bilateral. Coloured discharge is more
likely with an infective cause. When and where
symptoms appear is crucial to making a diagnosis. A patient may know that when they are near a
cat, they become symptomatic, or that they have
problems only in the summer suggesting a grass
pollen allergy. Symptoms all year round with a
blocked nose worse in the morning may suggest
HDM as the underlying cause.
As shown in Fig.20.4, the Allergic Rhinitis
and its Impact on Asthma (ARIA) classication
groups patients by their symptom duration and
severity. If a patient has one or more of the symptoms that affect quality of life (disturbed sleep,
impairment of daily life and so on), then they are
categorised as having moderate to severe disease
and will be treated as such.
A more formal assessment of quality of life can
be made with a variety of tools such as the 36-Item
Short Form Health Survey (SF-36) (36- Item Short
Form Survey Instrument (SF- 36) | RAND) or
more specic questionnaires for patients with
nasal disease such as the Rhinoconjunctivitis
Quality of Life Questionnaire (RQLQ) (Qoltech-
Measurement of Health- Related Quality of Life &
Asthma Control) or the 22-item Sinonasal
Outcome Test (SNOT-22) (SNOT22.pdf (canvasc.
ca)). These tests can be useful in clinical practice
to understand the wider problems patients may
have and to document their response to treatment.
Endoscopic nasal examination should also be
undertaken, but is often most useful in excluding
pathologies other than AR. The classic visual
description of AR is of congested inferior turbinates, which have a pink or bluish tinge, and a
clear or slightly sticky mucus. Depending on disease activity at the time of examination, these
features may or may not be seen and their absence
is not useful in the diagnosis. Endoscopy should
exclude other causes such as nasal polyps,
chronic infective rhinosinusitis or enlarged adenoids. Signs of concern such as septal perforation
and bleeding or crusting may suggest a vasculitis,
and a unilateral mass that could be a tumour.
Examination of the mouth and eyes may show
the secondary effects of nasal block (with mouth
breathing or a dry mouth) and a history of asthma
or wheeze should prompt respiratory investigation as required.
Diagnostic Tests
The diagnosis of AR is made when the symptom
complex ts the diagnosis and is conrmed by
the presence (directly or indirectly) of specic
IgE causing allergy. In practice, most patients in
the community will be treated on the basis of a
classic history and perhaps an anterior nasal
examination without any diagnostic testing.
Patients referred for ENT or allergy advice, however, may have more severe or difcult to treat
symptoms and for them diagnostic tests may be
useful to allow more specic advice and
treatment.
Skin prick tests (SPTs) are the mainstay of
diagnosis. They are quick to perform and allow a
rapid diagnosis but do need trained staff to perform them. It is also possible then to advise the
patient on avoidance measures and to check that
they are using medications correctly. As a rapid
screen the patient should be tested, at a minimum, against the most common allergens of
grass pollen, dog, cat and HDM, as well as other
possible allergens that are suggested by the history (and a positive and negative prick test). This
will pick up the vast majority of the allergens
commonly found (Note: these may not be appropriate as a screen outside Europe). Remember,
the positive SPT must be correlated with the
patient’s symptoms to be useful and if several are
positive it may be that only one or two are clinically relevant.
The other commonly used test is to measure
serum IgE levels. Commonly called a RAST
(radioallergosorbent test), this is now more commonly performed as a uoroenzymatic immunoassay (FEIA). Elevated total IgE levels may
indicate an underlying allergic process, but specic IgE is needed to specify the allergen(s)
involved. It is more expensive than an SPT but
only requires a blood sample to be taken. This
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test may be useful if there are reasons why an
SPT cannot be performed, such as a lack of
trained staff, skin disease, patient anxiety or
severe allergic reactions in the past.
Other tests that can be performed are usually
not required but include CT scanning of the nose
and paranasal sinuses if there is doubt about the
ndings of the nasal examination or other concerns. Nasal airow can be roughly assessed by
looking at the vapour pattern produced on a cold
metal surface or tested more accurately by rhinomanometry, rhinospirometry or peak nasal inspiratory ow, and nasal anatomy with acoustic
rhinometry. Nasal provocation tests measure
symptoms following controlled allergen exposure, such as a reduction in nasal airow and an
increase in sneezing and running. Nasal cytology
may be used to assess inammatory cells in the
nasal mucus, looking specically for eosinophils,
which may suggest a non-allergic cause such as
non-allergic rhinitis with eosinophilia syndrome
(NARES). While these tests are all available, their
use is limited in the diagnosis of most patients.
except the presence of rhinitis and a negative test
for allergy. Patients should have nasal endoscopy
performed to exclude physical abnormalities,
chronic infection, tumour or nasal polyps as
would happen for AR.Some tests, such as measurement of eosinophils in nasal mucus, may
help but non-allergic rhinitis is often a diagnosis
of exclusion.
Treatment ofAR (Including
Immunotherapy)
The sites of action of the various drugs for managing AR are summarised in Fig.20.5.
The treatment of AR can be divided into a
hierarchy:
• Avoidance (or reduction of exposure)
• Symptomatic treatment
• Modication of the disease process
Avoidance
Dierential Diagnoses
Having taken a history, performed an examination and had conrmation of positive tests for
allergy, the diagnosis may be made with some
condence. Occasionally, however, there may be
some uncertainty and other diagnoses should be
considered and excluded.
Non-allergic rhinitis may have a number of
underlying causes. The commoner forms may be
summarised as:
• Idiopathic rhinitis (vasomotor rhinitis)
• Non-allergic occupational rhinitis
• Hormonal rhinitis
• Drug-induced rhinitis
• Non-allergic rhinitis with eosinophilia syn-
drome (NARES)
• Chemical rhinitis
• Atrophic rhinitis
The history, symptoms and likelihood of
exposure will often point toward a diagnosis but
there is no specic test for non-allergic rhinitis,
Avoidance sounds like the ideal method of controlling symptoms but can be difcult to achieve
in practice. If a specic allergen has been determined, then it may be worth making an attempt to
reduce exposure.
Tree and grass pollen, which is spread by the
wind, is widespread in the appropriate season and
can be difcult to avoid. Remaining indoors, or in
a car with good air ltration, can help but may
not always be possible. Changing clothes on
returning home to reduce pollen exposure (or
other allergens such as horse if the patient is a
rider) can help, as can the use of a saline nasal
spray or rinse to physically remove the allergen.
Pet allergens are persistent and will be widespread within a house. Obviously not having a
pet reduces exposure but washing hands after
contact and keeping dogs and cats out of the bedroom may be useful.
House dust mites are found in high levels in
pillows and mattresses and an anti-allergen cover
may be purchased to reduce levels. Switching
curtains to blinds and carpets to hard ooring
may also reduce numbers. Unfortunately,
Early phase reaction
antibodies
imation, etc.
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Antigen
crosslinking
Binding
IgE
Mabs to IgE
Late phase reaction
Mast cell
Th2 cell
Degranulation
stabilizers
Release of
cytokines
(IL-3, IL-4,
IL-5, GM-CSF)
Corticosteroids
Mast cell
Eosinophil
activation and
recruitment
Antileukotrienes
LeukotrienesLeukotriene
Histamine
Antihistamines
eosinophil peroxidase
monobasic protein
eosinophil cationic
protein cytokines
(IL-4, IL-5, IL-10,
GM-CSF, etc.)
Humanised monoclonal
receptor
Histamine
receptor
vasodilatation
vascular leakage
smooth muscle
spasm
mucosal edema
epithelial damage
leukocyte infiltration
sneezing
rhinorrhea
lacr
261
Fig. 20.5 The sites of action of medications for managing AR (reproduced with permission from Elsevier, with minor
addition)
although levels may be reduced using these methods, the evidence that they have a signicant
clinical effect is weak.
by appropriate pesticides and attention to damp
within the home.
Symptomatic Treatment
The vast majority of patients with AR will be
treated symptomatically, mostly with a combination of topical corticosteroids and topical or oral
antihistamines. The ARIA guideline for suggested treatment from 2008 [5] is summarised in
Fig. 20.6, and a possible update using visual
analogue scores (VAS) to assess symptom control in Fig.20.7 [6].
Antihistamines
Second-generation, non-sedating oral antihistamines such as cetirizine and loratadine may
be effective in controlling symptoms such as
sneezing and itching. They have a rapid onset of
Cockroach and mould levels can be controlled
action and are safe for long-term use. They have
no signicant effect on the symptom of block.
More benet is usually found if they are taken
before symptoms appear (i.e. for hay fever sufferers to start treatment before the appropriate
pollen season begins and the patient becomes
symptomatic).
Topical antihistamines such as azelastine
(often combined in a spray with uticasone) have
a rapid onset of action and the combined treatment is more effective than a nasal steroid alone.
Azelastine eyedrops may also help with itching of the eyes.
Leukotriene Receptor Antagonists
(LTRA)
Montelukast is the main LTRA used in AR.
It blocks the effect of some leukotrienes that
are synthesised after mast cell degranulation.
Leukotrienes promote inammation and increase
vascular permeability contributing to the symptoms of blockage and running. Montelukast
seems to have a clinical effect similar to loratadine but is less effective on block than a topical
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Diagnosis of allergic rhinitis
Intermittent
symptoms
Persistent
symptoms
Q. Gardiner
Check for asthma
especially in patients with severe
and/or persistent rhinitis
Mild
Not in preferred order
oral H
blocker
1
or intranasal H
and/or decongestant
or LTRA*
-blocker
1
Moderate-
severe
Not in preferred order
blocker
oral H
1
or intranasal H
and/or decongestant
or intranasal CS
or LTRA*
(or chromone)
In persistent rhinitis
review the patient
If failure: step-up
If improved: continue
for 1 month
-blocker
1
after 2–4 weeks
Mild
Moderate-
severe
In preferred order
intranasal CS
blocker or LTRA*
H
1
Review the patient
after 2-4 wks
Improved
Step-down
and continue
treatment
for >1 month
Add or increase
intranasal CS
dose
Failure
Review diagnosis
Review compliance
Query infections
or other causes
Rhinorrhea
add ipratropium
Allergen and irritant avoidance may be appropriate
If conjunctivitis
Add
oral H1-blocker
or intraocular H
or intraocular cromone
(or saline)
-blocker
1
Consider specific immunotherapy
Blockage
add
decongestant
or oral CS
(short term)
Failure
referral to specialist
Fig. 20.6 Recommendations of the ARIA update 2008 (CS corticosteroid, LTRA leukotriene receptor antagonist)
(reproduced with permission from Elsevier)
steroid. Not all patients get a signicant response
to LTRAs, but a trial of treatment can be worthwhile for some.
Sodium Cromoglicate
Mast cell stabilisers such as chromones are now
hardly used in the nose as the have a very limited
clinical effect, but cromoglicate eyedrops may
relieve allergic conjunctivitis.
Intranasal Glucocorticosteroids
Beclometasone, uticasone, triamcinolone and
mometasone are some of the more commonly
used intranasal corticosteroids.
They are used topically at the lowest necessary dose to limit the side effect prole. They
reduce all the symptoms of AR, including
blockage.
They work by inhibiting inammatory gene
transcription in the cell nucleus (among other
actions) and therefore take some time to have an
effect.
Patients should be advised that the effect will
not be immediate and that they may have to stay
on treatment for signicant lengths of time as the
drugs do not ‘cure’ the allergy but suppress it
during allergen exposure. A side effect of epistaxis is usually due to incorrect use of the spray
a
b
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VAS < 5
Initiate treatment
VAS < 5
If symptomatic: continue treatment
If no symptoms: consider step down
VAS < 5
Re-assess VAS daily up to D3
Step up and Re-assess VAS daily up to D7
VAS < 5
VAS ≥ 5
Initiate treatment
VAS ≥ 5
VAS ≥ 5
Consider SIT
VAS ≥ 5
Step-up treatment
Re-assess VAS daily up to D7
Re-assess VAS daily up to D3
VAS < 5
If symptomatic: continue treatment
If no symptoms: consider step down
VAS ≥ 5
Fig. 20.7 Proposed update to the ARIA guideline, 2020.
Step-up algorithm in untreated (a) and treated (b) patients
using VAS to assess symptoms. ‘ANY’ means any one
treatment selected from the adjacent box in the algorithm
marked rst line of the treating practitioner’s choice. Anti
H1 Oral antihistamine, INCS Intranasal corticosteroid,
AZE Azelastine, SIT Specic immunotherapy (reproduced
with permission from Elsevier)
VAS < 5
VAS ≥ 5
Step up and
Re-assess VAS daily
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and patient education will usually allow resolution of the problem.
Ipratropium
Topical ipratropium spray, an anticholinergic, can
be added to treatment with a topical steroid if the
patient complains of continuing rhinorrhoea. The
dose can be titrated to the patient’s symptoms.
Monoclonal Antibodies
A variety of humanised monoclonal antibodies
are now becoming available for the treatment of
allergic disease and work in a variety of ways.
Omalizumab binds to circulating IgE, thus
inhibiting it from binding to mast cells. This both
prevents mast cell degranulation and also reduces
cellular expression of IgE binding sites, therefore
giving a longer mode of action. It is generally
only used for patients with severe AR and asthma.
Mepolizumab, reslizumab and benralizumab
block IL5 (or the IL5 receptor), thus preventing
the function of this pro-inammatory cytokine.
Dupilumab targets the receptor for IL4 and
IL13, again stopping the actions of these cytokines. These drugs are not widely used yet for the
treatment of AR but it seems likely that targeted
treatments for individual patients will become
more commonly used in the future.
Surgery
There is a limited role for surgical intervention in
AR. Occasionally, there are patients who have
developed a xed hypertrophy of the nasal
mucosa with a block that does not improve even
with decongestion. Reduction of the bulk of the
inferior turbinates may allow an improvement in
nasal airow and a consequent increase in the
ability of topical steroids to penetrate into the
nasal cavities to control inammation.
to it. It is the only treatment known currently that
can rebalance the disordered immune system in
AR and modify the progression of allergic disease.
The regular administration of an allergen, either
subcutaneously (SCIT) or sublingually (SLIT),
causes the production of regulatory T cells (Treg)
that switch the immune response from the excess
production of Th2 cells to a Th1 prole. There is
also a production of IgG4 that acts as a blocking
antibody-preventing IgE binding. Both these
mechanisms result in a reduction of the allergic
reaction following subsequent allergen exposure.
After a 3-year course of treatment, patients should
experience a long-lasting reduction in symptoms
and a halt in disease progression. Efcacy rates
vary between different trials, but most patients
would expect to have a reduction in symptoms and
medication use of approximately 30% [7].
Immunotherapy is generally only used for
patients with more severe disease, which cannot
be controlled by standard medication [8]. It does
have a small risk of causing anaphylaxis and
therefore should only be prescribed by a practitioner experienced in its use and with the necessary resuscitation facilities available.
SCIT is usually given in two phases: induction, with a gradually increasing dose often given
weekly, followed by a maintenance phase with
injections every few weeks over a period not less
than 3years.
SLIT may be made up as drops or soluble tablets and may not need an induction phase. The
allergen given is taken up by antigen-presenting
cells in the oral mucosa and then works in much
the same way as SCIT, with a similar efcacy.
Treatment should also be given over a 3-year
period to give long-lasting tolerance and symptom control.
Modication oftheDisease Process
Immunotherapy
Immunotherapy (sometimes termed desensitisation) refers to a process whereby a patient develops tolerance to an allergen and therefore no
longer exhibits an allergic reaction when exposed
Children withAR
The term the atopic (or allergic) march refers to
the progressive development of allergic symptoms in childhood onwards. This starts with
atopic dermatitis (allergic eczema) and may
progress rst to short-lasting food allergy and
then to allergic asthma and AR (Fig.20.8).
Incidence (%)
Eczema
The Atopic Match
Rhinitis Asthma Food Allergy
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14
12
10
8
6
4
2
0
0510
Fig. 20.8 The atopic march—progressive development of allergy (reproduced with permission from Elsevier)
18 50 70 Ye ars
265
The presence of eczema in a young child may
predict further allergies developing in later life,
but only in 30–50% of affected children, so the
link between atopic dermatitis and other allergies
is complex. Whether the epithelial breakdown in
eczema allows sensitisation to allergens in individuals predisposed to allergy, or whether the
atopic march is a systemic dysfunction that manifests differently at different ages, is unclear.
Children will usually have several episodes
of viral acute infective rhinitis in a year, and as
one may immediately follow another, it can be
difcult to differentiate from an ongoing AR.If
there is itching and sneezing, or a seasonal or
environmental difference, then allergy is more
likely. A coloured nasal discharge means infection is more likely, either an infective rhinitis or
adenoiditis. Chronic infective rhinosinusitis is
unusual in children. SPTs may help to give a
diagnosis.
The treatment guidelines for children are similar to those for adults. Fluticasone can be used
from 4 years; mometasone and triamcinolone
from 6years. It is preferred not to use beclometa-
sone in younger children as it has a greater systemic bioavailability and may cause growth
retardation in higher doses.
Treatment with immunotherapy is useful in
children to reduce symptoms and to prevent the
atopic march but its availability at present is
unfortunately limited in many countries.
Areas ofControversy or Uncertainty
• What are the underlying causes of the increase
in allergic disease seen in the industrialised
world?
• Can we effectively change our environment to
reduce allergic disease?
• What is the role of parasitic infection in modi-
fying allergic disease?
• What combinations of treatment are best for
managing patients with AR and asthma?
• What will be the role for monoclonal antibod-
ies in AR?
• Should immunotherapy be more widely avail-
able, especially for children?
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Key Learning Points
• AR is a common disease that may have a signicant impact on quality of life and is frequently poorly managed.
• AR is part of a systemic disease termed the
unied allergic airway and is often associated
with asthma.
• Diagnosis is based on correlating typical
symptoms with tests for specic IgE (either
SPTs or serum IgE).
• Contemporary management is with avoidance
and antihistamines and topical steroids, but
immunotherapy and humanised monoclonal
antibodies may have increasing roles.
References
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